The invention described herein was supported by National Institute of Health Grant #ROICA40406.
The present invention relates to the identification and use of monoclonal antibodies specific for the glycoprotein antigen complex carrying the CA 125 epitope.
CA 125 is an antigenic determinant or epitope located on the surface of ovarian tumor cells with essentially no expression in normal adult ovarian tissue. However, CA 125 is expressed on the cell surface of tumor cells in culture and on ovarian tumor lesions. Significantly, CA 125 is elevated in the sera of patients (>90%) with ovarian adenocarcinoma. In fact, CA 125 is regularly detected on the tumor cell surface and in the serum of patients with serous cystadenocarcinoma of the ovary (>95%). Expression of this antigen occurs less frequently in endometrial and clear cell carcinomas, and essentially no expression is detected in mucinous cystadenocarcinomas. Although not exclusively found in the blood of these patients, CA 125 has been detected in the sera of a significant percentage of patients with pancreatic carcinoma (approximately 50%) and with liver and colon carcinoma (approximately 22–32%).
The presence of CA 125 in high concentrations in the serum of patients with ovarian adenocarcinoma has been widely used by health care providers in the treatment and management of such patients. Although CA 125 is not specific for ovarian carcinoma, there is, nonetheless, a direct correlation between the presence of CA 125 and disease status i.e., progression, regression, or no change. Since almost all ovarian cancer patients receive extensive chemotherapy, CA 125 is used as an indicator of a disease free state. Further, increased serum concentrations of CA 125 precede clinical diagnosis of recurrent disease by a period of approximately one to four months. As a result, assay of this tumor marker is becoming a standard diagnostic tool in monitoring ovarian cancer patients.
As previously described, CA 125 is not an exclusive product of ovarian cancer cells. Like many other tumor markers, CA 125 is also expressed normally in early fetal development. For example, Kabawat et al. (Int J Gynecol Pathol, 2:275–85 (1983)) demonstrates the presence of traces of CA 125 in fetal tissues; the antigen was localized to the amnion and derivatives of muellerian epithelium, and coelomic epithelium (including the peritoneum, pleura and pericardium). In adult tissues, Kabawat et al. and Hardardottir et al. (Am J Obstet Gynecol, 163:1925–1931 (1990)) report that the monoclonal antibody, OC 125, reacts with the epithelium of the fallopian tube, endometrium, and endocervix, and is also expressed in the apocrine sweat glands and the mammary glands. Hardardottir et al. further discloses the presence of CA 125 antigen during fetal development in notochord, myocardium, pericardium, the mesonephric duct, the vitelline and allantoic ducts, as well as the amnion and periderm. Elevations of serum CA 125 in patients with endometriosis, during menses, and in early gestation further demonstrates expression of this antigen during normal growth and development. The abundance of the antigen in breast milk, benign ovarian cyst fluid, and amniotic fluid further implicate CA 125 in normal cell growth and development.
Little is known of the structure of the CA 125 antigen or the metabolic regulation or expression of this antigen in either normal or neoplastic tissues. Current state of the art discloses that CA 125 is part of a large molecular weight mucin-like glycoprotein complex, which can be resolved to a 200 kd–250 kd species on SDS acrylamide or agarose-acrylamide gels. Based on the presence of sugar residues, buoyant density studies, and lectin binding properties, the CA 125 antigen is thought to contain a carbohydrate component. However, the antigenic epitope that is recognized by the monoclonal antibody, OC 125, is considered to be peptidic in nature, because of its sensitivity to proteases like trypsin and V8 protease and its relative stability to glycosidases.
It would be highly desirable to gain a better understanding of the structure and function of the CA 125 antigen, especially through the development of new reagents to map protein domains. The development of new reagents such as monoclonal antibodies would likely provide a basis for new immunoassays with improved sensitivity and specificity for the detection of CA 125 antigen.